Opioid receptors (ORs) mediate the actions of morphine and morphine-like opioids, including most clinical analgesics. Three molecularly and pharmacologically distinct opioid receptor types have been described: δ, κ and μ. Furthermore, each type is believed to have sub-types. All three of these opioid receptor types appear to share the same functional mechanisms at a cellular level. For example, activation of the opioid receptors causes inhibition of adenylate cyclase, and recruits β-arrestin.
When therapeutic doses of morphine are given to patients with pain, the patients report that the pain is less intense, less discomforting, or entirely gone. In addition to experiencing relief of distress, some patients experience euphoria. However, when morphine in a selected pain-relieving dose is given to a pain-free individual, the experience is not always pleasant; nausea is common, and vomiting may also occur. Drowsiness, inability to concentrate, difficulty in mentation, apathy, lessened physical activity, reduced visual acuity, and lethargy may ensue. Additionally, those administered morphine and similar non-biased ligands can suffer from hyperalgesia. If the cause is due to an opioid therapeutic, it can be referred to as Opioid Induced Hyperalgesia (OIH).
There is a continuing need for new OR modulators to be used as therapeutics that do not cause hyperalgesia or that can be used to treat people that suffer from hyperalgesia, induced by opioids or otherwise. The present embodiments satisfy these needs as well as other.